According to the WHO there is a global "diabetes epidemic." In the United States alone, the cost of diabetes in 2007 was estimated at $174 billion. Much of this expense is due to the many problems that accompany type 2 diabetes, including vascular disease and increased risk for cognitive impairments, which may limit activities of daily living and the patients' ability to comply with treatments. However, little is known about the relative contributions of genetics, environment, and diabetes-associated factors such as vascular disease to cardiovascular, genetic, epidemiological, and state of the art brain imaging methods for 1200 subjects in a diabetes-enriched population. The proposal has three specific aims that combine the applicant's neuroscience background with the mentor's extensive epidemiological and genetic experience: 1) Identify brain regions that exhibit an association with T2DM during a working memory task using functional MRI; 2) [unreadable] Assess epidemiological relationships between MRI measures within pre-defined regions of interest and [unreadable] measures of cognition, cerebrovascular health, physical characteristics, and extensive previously acquired measures of cardiovascular disease; 3) Perform heritability and single nucleotide polymorphism (SNP) association analyses. Subjects will be recruited from a previous study of diabetes and cardiovascular disease where extensive genetic and cardiovascular measures were acquired and will complete a cognitive test battery, clinical tests (e.g., fasting blood glucose), and MR imaging scans that will allow assessment of white matter integrity, cerebral perfusion, brain volume, and neural activity. Voxel-wise whole brain analyses will be performed on the fMRI data; generalized estimating equations will be used to model epidemiological relationships between MR-derived data, cardiovascular and clinical measures, physical characteristics, and cognition; and the heritability of functional MRI measures will be estimated taking into account the influence of characteristics identified in the epidemiological analysis. The extensive genetic database derived from prior DNA analysis will be used to assess single nucleotide polymorphism association of MRI traits. Globally and in the US, diabetes has reached epidemic proportions. This study aims to integrate state of the art cognitive, imaging, and genetics techniques to learn more about why type 2 diabetes increases the risk for cognitive impairments. This information is important to establish the biological causes for diabetesrelated cognitive decline, design effective treatments and inform preventative strategies. [unreadable] [unreadable] [unreadable] [unreadable]